1. Field of the Invention
The present invention relates to a liposome composition and a method for producing the same. The present invention relates to a liposome composition which can be preferably used for pharmaceutical applications and a method for producing the same.
2. Description of the Related Art
A liposome (hereinafter, also referred to as lipid vesicle) is a closed vesicle formed of a lipid bilayer membrane using lipids, and has a water phase (inner water phase) within the space of the closed vesicle. Liposomes are usually present in a state of being dispersed in an aqueous solution (outer water phase) outside the closed vesicle. Liposomes have been studied for a variety of applications such as immune sensors, artificial red blood cells, and carriers of drug delivery systems taking advantage of features such as barrier capacity, compound retention capacity, biocompatibility, the degree of freedom of setting the particle size, ready biodegradability, and surface-modifying properties. In carrier applications, liposomes can encapsulate water-soluble compounds, lipophilic low-molecular weight materials, polymers and a wide range of materials.
In the case where liposomes are used particularly as a carrier for a drug delivery system, it is necessary to make a particle size to be about 200 nm or less in terms of permeation through a biological membrane. Further, in a carrier for a drug delivery system, it is also necessary to have liposomes which form particles having a good dispersibility under the temperature conditions of about 37° C. which is the body temperature of a mammal. In particular, with regard to nano-sized fine particles, it is preferred to impart preservation stability from various viewpoints such as aggregation, precipitation, and leakage of drugs.
As a carrier for a drug delivery system, in the case where a drug (solution or the like containing liposomes containing a drug) is administered by intravenous injection, high safety is required for an intravenous injection product. Additives such as chlorinated solvents, for example chloroform, or dispersing aids whose use are not allowed are undesirable. In addition, impartment of stability to a pharmaceutical product is also necessary, and correspondingly suppression of drug leakage, lipid decomposition or the like after storage is required. Further, suitability for sterile filtration is also required in order to guarantee sterility. When it is desired to produce liposomes as a pharmaceutical product on an industrial scale, it is necessary to take into account the requirements as described above.
JP2006-522026A discloses a composition containing liposomes stably associated with at least one water-soluble camptothecin and at least one fluoropyrimidine, in which a molar ratio of camptothecin:fluoropyrimidine has desired cytotoxic, cytostatic, or biological effects on cells or cancer cell homogenates. Moreover, this document discloses that the liposomes contain cholesterol which is present in an amount of less than 20 mol %. However, there is no description about an osmotic pressure in an outer water phase and an inner water phase of the liposomes.
JP2013-512262A discloses a liposome containing irinotecan or irinotecan hydrochloride, neutral phospholipids and cholesterol, in which a weight ratio of cholesterol:neutral phospholipids is 1:3 to 5. In addition, there is a description that the liposome contains irinotecan hydrochloride, hydrogenated soybean phosphatidylcholine, polyethylene glycol 2000-distearoyl-phosphatidylethanolamine, and cholesterol in a component weight ratio of 1:3.4 to 3.8:0.34 to 0.38:0.8 to 0.95. However, there is no clear description about an osmotic pressure in the outer water phase and the inner water phase of the liposome. Although such a liposome has an ionic gradient, which is formed by a buffer, between the inner water phase and the outer water phase of the liposome, there is a possibility that the inner water phase may be hyper-osmotic relative to the outer water phase because a drug is loaded. However, since a certain amount of ions are leaked during the loading of a drug, it can be assumed that the ionic gradient difference is not large. In addition, when such a component weight ratio is converted with respect to the total amount of lipid components in the liposome composition, the content of cholesterol corresponds to an amount of 29 mol % to 36 mol %. According to this conversion, the molecular weight of hydrogenated phosphatidylcholine, polyethylene glycol 2000-distearoyl-phosphatidylethanolamine, and cholesterol was calculated to be 785, 2730, and 387, respectively. It should be noted that the converted values are the minimum and maximum percentages of cholesterol that can be taken in the above-mentioned individual component weight ratio range.
In all of the above-mentioned documents, a liposome composition having a practically required long-term preservation stability and also having a suitable release rate and a method for producing the same have not been fully established, and correspondingly improvements are desired.